The CNS remains a target of HIV in the era of HAART, and the effects of CNS dysfunction can be devastating. The SIV-infected monkey model for HlV-related diseases has been invaluable in studies of HIV/AIDS pathogenesis and treatment/vaccine research. We and others have developed systems and techniques to enable the study of CNS disease in SIV-infected monkeys. Using brain RNA from different stages of SIV-induced disease, we have found distinct alterations in the transcriptional profile both during the stable phase of disease, when animals are generally asymptomatic but have measurable CNS functional abnormalities, as well as in end-stage neurological disease. Here, we will first investigate 2 mechanisms for neuronal damage identified from alterations in neuronal gene expression in microarray studies. Second, using a recently developed HAART protocol, we will now study CNS function and changes in CNS gene expression during HAART treatment of SIV-infected monkeys. Furthermore, we have developed methodologies for metabolomic analysis, enabling us to perform a longitudinal study to identify significant biomarkers in plasma and CSF that correlate with CNS disease. These experiments will yield novel data, and lead to the identification of unique molecules that can then be examined in humans, as well as provide the starting point for new studies aimed at the sources of the identified metabolic differences. The identification of molecular markers for neuroAIDS is valuable for both diagnostic and etiopathogenic reasons, and we believe the recent developments in metabolomics give these techniques a distinct advantage in achieving this goal.